Pd(II)-Catalysed Cyclisations of Aminoalkenitols Dr. Peter Szolcsányi Department of Organic Chemistry Slovak University of Technology Bratislava, Slovak.

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Presentation transcript:

Pd(II)-Catalysed Cyclisations of Aminoalkenitols Dr. Peter Szolcsányi Department of Organic Chemistry Slovak University of Technology Bratislava, Slovak Republic

Pd(II)-Catalysed chlorocyclisation and N,O-bicyclisation of polyhydroxylated aminoalkenitols

Synthetic versatility of chloromethyl piperidines

Structural diversity of piperidine/azepine alkaloids

Where did the idea come from ? P. Szolcsányi et al.: Tetrahedron: Asymmetry 2000, 11,

Substrates for the screening

Preparation of substrates - D-gluco serie

Preparation of substrates - D-galacto serie

Pd(II)/CuCl 2 -catalysed chlorocyclisation-D-gluco serie EntrySolventTime & Temperature Isolated yield (after FLC) HPLC ratio of L-ido / D-gluco (d.e.) 1AcOH48 hrs, 23 o C70%19 / 1 (90%) 2DMF24 hrs, 30 o C21% 8 / 1 (82%) 3CH 2 Cl 2 24 hrs, 30 o C65% 6 / 1 (71%) 4THF24 hrs, 30 o C60%6 / 1 (71%) 5MeOH24 hrs, 23°C59%5 / 1 (67%) 6Toluene48 hrs, 30 o C56% 3 / 1 (33%)

Pd(II)/CuCl 2 -catalysed chlorocyclisation-D-galacto serie EntrySolventCatalyst & Additive(s) Time & Temperature Chlorides/bicycle (yield after FLC) HPLC ratio of L-altro/D-gala (d.e.) 1AcOH0.1 eq. PdCl 2, 3 eq. CuCl 2, 3 eq. AcONa24 hrs, 25 o C28% / 49%19 / 1 (90%) 2DMF- detto -19 hrs, 25 o C53% / 11%15 / 1 (88%) 3CH 2 Cl 2 - detto -24 hrs, 29 o C36% / 8% 5 / 1 (67%) 4THF- detto -24 hrs, 25 o C54% / 10%2 / 1 (33%) 5Toluene- detto -24 hrs, 29 o C43% / 9%1 / 2 (33%) 6MeOH- detto -24 hrs, 25 o C32% / 7%1 / 3 (50%) 7AcOH0.1 eq. PdCl 2, 2 eq. CuCl 2, 2 eq. AcONa48 hrs, 30 o C35% / 52%19 / 1 (90%) 8AcOH0.1 eq. PdCl 2, 1 eq. CuCl 2, 1 eq. AcONa48 hrs, 28 o C25% / 48%19 / 1 (90%) 9AcOH0.1 eq. PdCl 2, 3 eq. CuCl 2 24 hrs, 30 o C27% / 50%19 / 1 (90%) 10AcOH1 eq. PdCl 2, 3 eq. AcONa96 hrs, 28 o C0% / 0%- 11AcOH0.1 eq. Pd(OAc) 2, 2 eq. BQ, 3 eq. AcONa24 hrs, 30 o C- / 0%-

Mechanistic proposal of the Pd(II)/CuCl 2 -catalysed chloroaminocyclisation and bicyclisation

Synthesis of new analogues of iminoalditols P. Szolcsányi, T. Gracza: Tetrahedron 2006, 62,

Conclusions We have found a novel Pd(II)-catalysed halocyclisation and/or bicyclisation We have found a novel Pd(II)-catalysed halocyclisation and/or bicyclisation of aminoalkenitols providing chloromethyl-piperidines and/or oxa- of aminoalkenitols providing chloromethyl-piperidines and/or oxa- azabicyclo[3.2.1]octanes azabicyclo[3.2.1]octanes We have postulated the reaction mechanism explaining the observed We have postulated the reaction mechanism explaining the observed chemoselectivity chemoselectivity Both transformations were developed into effective synthetic methodologies Both transformations were developed into effective synthetic methodologies that were successfully employed in the total synthesis of new analogues of that were successfully employed in the total synthesis of new analogues of glycosidase inhibitor 1-deoxynojirimycin glycosidase inhibitor 1-deoxynojirimycin

Acknowledgments Generous supportProf. Dr. Tibor Gracza HPLCDr. Katarína Hroboňová NMRDr. Naďa Prónayová IRMs. Silvia Markusová MALDIDr. Ivan Špánik GrantAPVT

Known precedents of Pd(II)/CuCl 2 -catalysed haloaminocyclisation yielding 6-membered azacycles

Known reports on Pd(II)/Cu(II)-heterobimetallic complexes